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Signal detection requires ratings reliability throughout a clinical trial. The confirmation of site-based rater scores by a second, independent and blinded rater is a reasonable metric of ratings reliability. We used audio-digital pens to record site-based interviews of the Montgomery-Asberg Depression Rating Scale (MADRS) in a double-blind, placebo controlled trial of a novel antidepressant in treatment resistant depressed patients. Blinded, site-independent raters generated "dual" scores that revealed high correlations between site-based and site-independent raters (r=0.940 for all ratings) and high sensitivity, specificity, predictive values, and kappa coefficients for treatment response and non-response outcomes using the site-based rater scores as the standard. The blinded raters achieved an 89.4% overall accuracy and 0.786 kappa for matching the treatment response or non-response outcomes of the site-based raters. A limitation of this method is that independent ratings depend on the quality of site-based interviews and patient responses to the site-based interviewers. Nonetheless, this quality assurance strategy may have broad applicability for studies that use subjective measures and wherever ratings reliability is a concern. "Dual" scoring of recorded site-based ratings can be a relatively unobtrusive surveillance strategy to confirm scores and to identify and remediate rater "outliers" during a study., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Band-pass filtering is a novel statistical methodology that proposes that filtering out data from trial sites generating non-plausible high or low levels of placebo response can yield a more accurate effect size and greater separation of active drug (when efficacious) from placebo. We applied band-pass filters to re-analyze data from a negative antidepressant trial (NCT00739908) evaluating CX157 (a reversible and selective monoamine oxidase inhibitor-A) versus placebo. 360 patients from 29 trial sites were randomized to either CX157 treatment (n=182) or placebo (n=178). We applied two filters of<3 or>7 points (filter #1) or<3 and>9 points (filter #2) mean change of the total MADRS placebo scores for each site. Trial sites that had mean placebo MADRS score changes exceeding the boundaries of these band-pass filter thresholds were considered non-informative and all of the data from these sites were excluded from the post-hoc re-analysis. The two band-pass filters reduced the sample of informative patients from 353 patients in the mITT population to 62 in filter #1 and 152 in the filter #2 group. The placebo response was reduced from 31.1% in the mITT population to 9.4% with filter #1 and 20.8% with filter #2. MMRM analysis revealed a non-statistically significant trend of p=0.13 and 0.16 for the two filters in contrast to the mITT population (p= 0.58). Our findings support the band-pass filter hypothesis and highlight issues related to site-based scoring variability and inappropriate subject selection that may contribute to trial failure., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Objectives: To compare the bacteriologic and clinical efficacy of amoxicillin/clavulanate and azithromycin in patients with acute otitis media (AOM), particularly the ability to eradicate the predominant AOM pathogens from middle ear fluid as assessed by mandatory second tympanocentesis., Methods: In this single blind study 238 infants and children with AOM were randomized to receive amoxicillin/clavulanate (45/6.4 mg/kg/day in two divided doses for 10 days) or azithromycin (10 mg/kg on Day 1, then 5 mg/kg daily on Days 2 through 5). Tympanocentesis was performed before the first dose and repeated on Day 4, 5 or 6. Clinical response was assessed at end of therapy between Days 12 and 14 and at follow-up between Days 22 and 28., Results: Amoxicillin/clavulanate was significantly more likely to eradicate all bacterial pathogens [83% (54 of 65) vs. 49% (35 of 71), P = 0.001] and Haemophilus influenzae [87% (26 of 30) vs. 39% (13 of 33), P = 0.0001] from middle ear fluid than was azithromycin. Amoxicillin/clavulanate was also more likely to eradicate Streptococcus pneumoniae, but the difference was not statistically significant [90% (18 of 20) vs. 68% (13 of 19) [corrected], P = 0.095]. On Days 12 to 14, signs and symptoms were more likely to resolve completely or improve in all culture-positive patients [86% (60 of 70) vs. 70% (51 of 73), P = 0.023] and in those with H. influenzae infections [91% (30 of 33) vs. 65% (22 of 34), P = 0.010] who received amoxicillin/clavulanate compared with those who received azithromycin. Otherwise there were no significant differences between groups in clinical outcomes on Days 12 to 14 or at follow-up., Conclusions: Our findings indicate that amoxicillin/clavulanate has superior bacteriologic and clinical efficacy compared with azithromycin in children with AOM.

Unlabelled: Respiratory syncytial virus (RSV) is a frequent cause of hospitalization among infants. To compare patient management in Europe, the United States, and Australia, we analyzed the charts of 1,563 pediatric patients hospitalized with laboratory-confirmed RSV lower respiratory infections during recent RSV seasons. Half of patients had been seen initially as outpatients. Median duration of hospitalization was 4 days in Australia, Finland, the United Kingdom, and the United States, and 8 or 9 days in Belgium, France, Germany, Italy, and the Netherlands. In a linear regression model that included clinical findings, underlying conditions, prematurity, and age, the leading variable associated with length of stay was "hospitalization in continental Europe". This geographic factor conferred a 1.8-fold longer stay (95% CI: 1.7-1.9) than hospitalization elsewhere. Utilization of nine supportive therapies for RSV varied widely among hospitals, even within the same country. The individual hospital was strongly associated with the use of every therapy studied, independent of patient characteristics and clinical status., Conclusion: Management of RSV patients varies markedly by country and hospital. Multicenter RSV trials that measure length of stay should standardize criteria for "readiness for discharge". It may be appropriate to limit international trials to countries with similar median stays for RSV. Variability within multicenter trials could be further controlled by standardizing the use of other therapies and the diagnosis of complications.

The management of acute otitis media is complicated by the emergence of resistance to beta-lactam and other antibiotics among common pathogens. We conducted a large, international study of infants and children with acute otitis media to identify pathogens and susceptibility patterns. During the winter of 1994 to 1995, middle ear fluid samples were collected from 917 patients with acute otitis media in Bulgaria, the Czech Republic, Hungary, Romania, Slovakia, Israel, and the United States. A single reference laboratory performed in vitro susceptibility testing. Pathogens were isolated from 62% of the patients. For Streptococcus pneumoniae (30% of the patients), untypeable Haemophilus influenzae (17%), and Moraxella catarrhalis (4%), there was significant variation among geographic regions (P < 0.001). The composite susceptibilities of these three organisms to amoxicillin ranged from 62% in the United States to 89% in Eastern and Central Europe; the corresponding susceptibilities to amoxicillin-clavulanate ranged from 90% in Israel to 95% in Eastern and Central Europe. beta-Lactamase was produced by 31 and 100% of the isolates of H. influenzae and M. catarrhalis, respectively. More isolates of S. pneumoniae were susceptible to amoxicillin (90%) or amoxicillin-clavulanate (90%) than to penicillin (70%; P = 0.002). The prevalence of resistant S. pneumoniae was highest in patients less than 12 months of age. S. pneumoniae, H. influenzae, and M. catarrhalis remain the most important bacterial pathogens in patients with acute otitis media; however, their prevalence is variable and resistance patterns are changing.

Objective: To compare the safety and efficacy, in treating acute otitis media (AOM) in children, of a new formulation of amoxicillin/clavulanate potassium (Augmentin) oral suspension providing 45/6.4 mg/kg/day and administered twice daily (bid) for 5 and 10 days, respectively, with the safety and efficacy of the original formulation providing 40/10 mg/kg/day and administered three times daily (tid) for 10 days., Study Design: Eight hundred sixty-eight children ages 2 months to 12 years with AOM were randomly assigned to one of the three treatment groups. Stringent criteria were used for the diagnosis of AOM and for determinations of "cure" and "improvement." Subjects were reexamined on Days 12 to 14 and 32 to 38., Results: Among subjects whose treatment and follow-up conformed fully to protocol, the proportion of treatment successes (clinically cured or improved) on Days 12 to 14 was 78.8% (149 of 189) in the tid 10-day group, 86.5% (154 of 178) in the bid 10-day group and 71.1% (140 of 197) in the bid 5-day group. Corresponding values on Days 32 to 38 were 64.2% (95 of 148) in the tid 10-day group, 63.1% (94 of 149) in the bid 10-day group and 57.8% (93 of 161) in the bid 5-day group. None of the differences between the tid 10-day regimen and either of the 2 bid regimens were statistically significant, but the bid 10-day regimen was significantly more effective than the bid 5-day regimen in younger subjects. In the study population as a whole, results were similar to those in per protocol subjects. Overall the incidence of protocol-defined diarrhea was 26.7% (74 of 277) in the tid 10-day group, compared with 9.6% (27 of 280) in the bid 10-day group (P < 0.0001) and 8.7% (25 of 286) in the bid 5-day group (P < 0.0001)., Conclusions: In comparison with the original formulation of Augmentin administered tid for 10 days in the treatment of AOM in children, the new formulation administered bid for 10 days provides at least equivalent efficacy and causes substantially less diarrhea. Administration for 5 days appears not to provide equivalent efficacy, but the difference appears limited to younger children and the margin of difference is small.

Objective: To establish the lowest dose of cyclical dydrogesterone that protects against endometrial hyperplasia induced by continuous 2 mg 17 beta oestradiol, and to study the dose effect on vaginal bleeding and side effects., Design: Double-blind, prospectively randomised dose-ranging study., Setting: Menopause clinics in the UK and The Netherlands., Subjects: Three hundred and seventy-one postmenopausal women with intact uteri, aged 40 to 60., Interventions: Administration of six 28-day treatment cycles of continuous daily micronised 17 beta oestradiol with a randomly allocated dose of 5 to 20 mg of dydrogesterone added for the last 14 days of each., Main Outcome Measures: Histological assessment of adequate progestational endometrial response, bleeding patterns and adverse effects., Results: The study was completed by 320 subjects (86%). Endometrial transformation occurred in over 94% of those taking 5 mg of dydrogesterone, and in over 97% of those on higher doses, without significant differences between the 10, 15 and 20 mg groups. Acceptable bleeding patterns were found at all doses, with the incidence of withdrawal bleeding rising with increasing dose. The day of onset of bleeding was predictable from cycle to cycle, and occurred later in the 20 mg group than in the others. The incidence of noncyclic bleeding was about 6% at all doses. Withdrawal occurred in 3.3% due to unacceptable bleeding and in 5.4% due to side effects. There was no relation with dose., Conclusions: A dydrogesterone-17 beta oestradiol combination hormone replacement therapy confers endometrial protection with an acceptable bleeding pattern and few side effects At least 10 mg of dydrogesterone for 14 days is required for acceptable endometrial protection.

A case of alveolar soft part sarcoma of the uterus is described. It presented as intermenstrual bleeding in a 47-year-old woman. This is a rare tumor, forming about 1% of soft tissue sarcomas. Several hundred cases have been described, mostly arising in the limbs. We believe this to be the 3rd case reported in the uterus and the 12th in the female genital tract. The other reported cases are reviewed, and further information about their outcome has been obtained from the authors.

Entamoeba histolytica is an intestinal parasite causing significant morbidity and mortality worldwide. More tools are needed to understand the epidemiology and molecular pathogenesis of amebiasis. A cDNA library was constructed by using poly(A)+ RNA isolated from an axenic strain of E. histolytica, HM1:IMSS, which expresses a pathogenic isoenzyme pattern (zymodeme). Differential screening of the library yielded a strain-specific 3' polyadenylated cDNA clone, C2, possessing nine 26-nucleotide tandem repeats. RNA and DNA transfer blot analysis of four axenic strains of E. histolytica possessing the same pathogenic zymodeme revealed that the gene is present and expressed in pathogenic E. histolytica HM1:IMSS and 200:NIH but is not present in pathogenic strains HK-9 and Rahman. In addition, Southern blot analysis using the C2 clone showed heterogeneity of genomic organization between HM1:IMSS and 200:NIH. DNA dot blot hybridization analysis demonstrated that cDNA clone C2 was also able to distinguish axenically cultured E. histolytica strains possessing pathogenic zymodemes from those possessing nonpathogenic zymodemes and could detect as few as 100 amebic trophozoites. We conclude that C2 is a strain-specific E. histolytica cDNA clone that, in conjunction with other E. histolytica-specific probes, could serve as a useful epidemiologic tool.